Following specification of neuronal fates, transcriptional mechanisms are thought to contribute to the production of a wide range of different neuronal morphologies. In mammals relatively little is known about how these morphogenic programs are regulated. Recent genetic evidence indicates that signaling by Ca2+, calcineurin and NFATc proteins is essential to generate a variety of specific axonal morphologies in mice. The studies described in this proposal are directed at understanding the mechanisms used by these molecules to generate specific patterns of axonal outgrowth that are essential for normal neural development. We will begin by defining the cell types in which the pathway functions. We will then define the developmental time period that the pathway is needed for specific patterns of axonal outgrowth. Since the phenotypes of mice with defects in this pathway suggest that it might respond to novel axonal guidance cues, we will define new ligands and receptors that activate NFAT in neurons. Axonal outgrowth is often accompanied by the production of complex architectures or specialized sensory structures suggesting some means of communicating local information from the growth cone to the nucleus to activate the genes essential for these specialized structures. NFATc proteins rapidly move from the axon and growth cone to the cell body after Ca2+ stimuli, implying that they could convey positional cues to the nucleus. We will define the mechanism of this transport and determine if it could allow rapid transcriptional monitoring of positional cues needed for specific axonal morphologies. Finally, we will develop a general method to rapidly and reversibly control the activity of any protein of interest in a mouse. We will then use this method to understand the functions of calcineurin and NFAT at critical times in the formation of specific axon morphologies. After completing our studies we expect to have defined a pathway beginning with ligand-receptor interactions through Ca2+, calcineurin and NFAT to the activation of target genes critical for specialized neuronal morphologies. We believe that this pathway, its target genes and its many modulators will be a rich source of new molecules for therapeutic intervention in neurologic diseases.